Topical treatments incorporating cannabis sp. derived botanical drug product

ABSTRACT

A topical formulation comprising a  Cannabis  derived botanical drug product, wherein the concentration of tetrahydrocannabinol, cannabidiol, or both in the topical formulation is greater than 2 milligrams per kilogram.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/914,064, filed on Mar. 7, 2018, which is a continuation of U.S.application Ser. No. 14/750,558 (abandoned), filed on Jun. 25, 2015,which is a continuation of U.S. application Ser. No. 14/498,555 (nowU.S. Pat. No. 9,095,563), filed on Sep. 26, 2014, which claims thebenefit of U.S. Provisional Application No. 61/882,990, filed on Sep.26, 2013, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to topical formulations that comprise a Cannabisderived botanical drug product, methods of making the topicalformulations, and methods of using the topical formulations in treatingdermatological diseases.

BACKGROUND OF THE INVENTION

The botanical genus Cannabis includes the species indica and sativia.Within these species multiple distinct varieties and strains have beenand continue to be developed. The genus known produce more than 480different chemical substances. Among these chemicals approximately 80distinct entities exist which are classified as cannabinoids. The twospecies differ in the amount of tetrahydrocannabinol (THC) produced.Cannabis sativia produces higher levels of THC. The psychotropic affectsassociated with THC have made the sativia species preferred as arecreational substance and for medicinal use where the psychotropiceffect is desired. Not-with-standing THC and other chemical entitiesproduced by the sativia species have significant and diversepharmacological action.

The indica species is cultivable in cooler climates and produce morecannabidiol (CBD) than THC. This allows production of extracts with lowTHC. The seeds from Cannabis species are used to produce hemp oil whichis used industrially and also as a nutritional supplement.

Cannabis derived materials which may contain THC and CBD in addition tonumerous natural substances produced by the plants have been reported tohave diverse pharmacological activities that include analgesic,anti-inflammatory, anti-cancer, antibiotic, and anti-oxidant activity.

In most jurisdictions throughout the world, including the United States,cannabinoids (which include THC, structurally related compounds, and insome instances CBD) are controlled substances and use for medicalpurposes has been discouraged. Since some products derived from cannabisspecies are economically important (e.g. hemp oil) maximum levels forcannabinoids in products have been set. In Canadian hemp seed oil THClevels are usually below detection limit of 4 ppm (parts per million, or4 mg/kg). Legal limit for THC content in foodstuffs in Canada is 10 ppm.Some European countries have limits of 5ppm or none-detected, some EUcountries do not have such limits at all.

Relaxation of laws limiting the use of marijuana and thus cannabinoidcontaining products, in some jurisdictions (e.g. as of 2013 medicalmarijuana is considered legal in 20 states and the District of Columbia)has opened the door to encourage development of new cannabinoidcontaining products. To a large extent major focus has been directed atsystemically administered formulations and formulations taking advantageof psychotropic activities or use of cannabinoids as antioxidants andneuroprotectants.

U.S. Pat. No. 6,630,507, incorporated herein by reference, disclosespharmaceutical compounds and compositions that are useful as tissueprotectants, such as neuroprotectants and cardioprotectants. Thecompounds and compositions are disclosed to be used in the treatment ofacute ischemic neurological insults or chronic neurodegenerativediseases. The disclosed compositions include cannabidiol and othercannabinoids, and the compositions are disclosed to include THC inamounts that do not promote psychoactive or psychotoxic effects.Accordingly, there is no disclosure of topical compositions that includeTHC in amounts that exceed the detection limit of THC.

In view of the foregoing, there is a need for topical formulations thatcomprise a Cannabis derived botanical drug product that take advantageof diverse pharmacologic activities, that are beyond and unforeseen fromthose described in U.S. Pat. No. 6,630,507 B1, in treatment ofdermatologic and other diseases. We also define that the majorcannabinoids are present in our products at concentrations exceeding thecommonly applied maximum levels that define cannabis derived products,such as hemp oil, legal for non-drug use can provide unexpected andhighly beneficial treatments for a wide variety of diseases.

BRIEF SUMMARY OF THE INVENTION

One object of the invention is to provide a topical preparationcomprising a Cannabis derived botanical drug product such that theconcentration of tetrahydrocannabinol in the final product is greaterthan 2 milligrams per kilogram. Other objects of the invention includemethods of making the topical preparations and methods of using thetopical preparations to treat dermatological diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an area of skin affected by plaque psoriasis.

FIG. 2 shows the results of treating psoriasis affected area byapplication of topical formulation comprising a Cannabis derivedbotanical drug product according to the present invention.

EMBODIMENTS OF THE PRESENT INVENTION

One embodiment of the present invention is [1] a topical formulationcomprising a Cannabis derived botanical drug product, wherein theconcentration of tetrahydrocannabinol in the topical formulation isgreater than 2 milligrams per kilogram.

Another embodiment of the present invention is [2] a topical formulationcomprising a Cannabis derived botanical drug product, wherein theconcentration of cannabidiol in the topical formulation is greater than2 milligrams per kilogram.

Another embodiment of the present invention is [3] a topical formulationcomprising a Cannabis derived botanical drug product, wherein theconcentration of each, cannabidiol and tetrahydrocannabinol, in thetopical formulation is greater than 2 milligrams per kilogram.

Another embodiment of the present invention is [4] a topical formulationaccording to [1], [2], or [3], which further comprises hydrocortisone orany steroid within Groups Ito VII in the US classification system in atherapeutically effective amount.

Another embodiment of the present invention is [5] a topical formulationaccording to [1], [2], or [3], which further comprises an antibioticcompound in a therapeutically effective amount.

Another embodiment of the present invention is [6] a topical formulationaccording to [1], [2], or [3], which further comprises an antisepticcompound in a therapeutically effective amount.

Another embodiment of the present invention is [7] a topical formulationaccording to [1], [2], or [3], which further comprises an antifungalcompound in a therapeutically effective amount.

Another embodiment of the present invention is [8] a topical formulationaccording to [1], [2], or [3], which further comprises an anti-acneagent in a therapeutically effective amount.

Another embodiment of the present invention is [9] a topical formulationaccording to [1], [2], or [3], which further comprises a soothing,smoothing, moisturizing or protective agent in a therapeuticallyeffective amount.

Another embodiment of the present invention is [10] a topicalformulation according to [1], [2], or [3], which further comprises aUV-absorbing compound in a therapeutically effective amount.

Another embodiment of the present invention is [11] a topicalformulation according to [1], [2], or [3], which further comprises ananalgesic compound in a therapeutically effective amount.

Another embodiment of the present invention is [12] a topicalformulation according to [1], [2], or [3], which further comprises ananti-viral compound in a therapeutically effective amount.

Another embodiment of the present invention is [13] a topicalformulation according to [1], [2], or [3], which is in the form of alotion.

Another embodiment of the present invention is [14] a topicalformulation according to [1], [2], or [3], which is in the form of acream.

Another embodiment of the present invention is [15] a topicalformulation according to [1], [2], or [3], which is in the form of asalve.

Another embodiment of the present invention is [16] a topicalformulation according to [1], [2], or [3], which is in the form of aliniment.

Another embodiment of the present invention is [17] a topicalformulation according to [1], [2], or [3], which is in the form of anointment. Another embodiment of the present invention is [18] a topicalformulation according to [1], [2], or [3], which is in the form of agel.

Another embodiment of the present invention is [19] a topicalformulation according to [1], [2], or [3], which is in the form of apaste.

Another embodiment of the present invention is [20] a topicalformulation according to [1], [2], or [3], which is in the form of atonic.

Another embodiment of the present invention is [21] a topicalformulation according to [1], [2], or [3], which is in the form of anunguent.

Another embodiment of the present invention is [22] a topicalformulation according to [1], [2], or [3], which is in the form of anasal spray. Another embodiment of the present invention is [23] atopical formulation according to [1], [2], or [3], which is in the formof a soap.

Another embodiment of the present invention is [24] a topicalformulation according to [1], [2], or [3], which is in the form of ashampoo.

Another embodiment of the present invention is [25] a topicalformulation according to [1], [2], or [3], which is in the form of a lipbalm.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, the indefinite articles “a” and “an” aresynonymous with “at least one” or “one or more.” Unless indicatedotherwise, definite articles used herein, such as “the,” also includethe plural of the noun. Terms used herein such as “comprising,”“consisting essentially of,” and “consisting of” have their ordinary andcustomary meaning under U.S. patent law. Unless otherwise indicated, thetransitional term “comprising” is synonymous with “including,”“containing,” or “characterized by” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method stages. Unlessotherwise indicated, the transitional term “consisting essentially of”limits the scope of the claim to the materials specified and/or recitedin the body of the claim or method stages specified and/or recited inthe body of the claim, and this transitional phrase excludes thosematerials or stages that materially affect the basic and novelcharacteristics of the claimed invention. Unless otherwise indicated,the transitional term “consisting of” limits the scope of the claim toonly those materials specified and/or recited in the body of the claimor to only those method stages specified and/or recited in the body ofthe claim.

The units for the concentration of compounds in topical formulations asused herein are typically represented as milligrams per kilogram, unlessotherwise indicated. Milligrams per kilogram is equal to parts permillion (“ppm”).

Unless otherwise indicated, the term “Cannabis” used herein refers to atleast one of Cannabis sativia and Cannabis indica. Some of the materialswhich are produced by the Cannabis species have been shown to havepharmacologic activity. Such materials are discussed in turn.

Tetrahydrocannabinol, which is abbreviated herein as “THC” unlessotherwise indicated, is the principal psychoactive constituent (orcannabinoid) of the cannabis plant. THC is also known asdelta-9-tetrahydrocannabinol (Δ9-THC). THC was first isolated in 1964,and, in its pure form, it is a glassy solid when cold and becomesviscous and sticky if warmed. Pharmaceutical formulations that compriseTHC, known by its INN dronabinol, are available by prescription in theU.S. and Canada under the brand name MARINOL. THC is an aromaticterpenoid, and it has a very low solubility in water but good solubilityin most organic solvents, specifically lipids and alcohols. THC alsoexhibits high UV-B (280-315 nm) absorbance.

Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.It is a major constituent of the plant, second to THC, and represents upto 40% in its extracts. Compared with THC, cannabidiol isnon-psychoactive, and is considered to have a wider scope of medicalapplications than THC, including to epilepsy, multiple sclerosis spasms,anxiety disorders, schizophrenia, nausea, convulsion and inflammation,as well as inhibiting cancer cell growth. CBD may decrease the rate ofTHC clearance from the body, perhaps by interfering with the metabolismof THC in the liver. CBD has displayed sedative effects in animal tests,while other studies have found that CBD may increases alertness. CBD hasbeen shown to reduce growth of aggressive human breast cancer cells invitro, and to reduce their invasiveness.

CBD is an anti-oxidant, has anti-inflammatory activity and analgesicproperties in animal studies. It has been shown to inhibit the growth ofbacteria, and is thought to exhibit psychoactive properties that aredistinct from THC that include anticonvulsant and anti-epilepticproperties.

Other pharmacological cannabinoid activities include (β-sitosterol,tocopherols, terpenes, methyl salicylate, hemp oil or hempseed oil, hashoil, and hashish. These are discussed in turn.

Beta-Sitosterol: Although studies have primarily demonstrated theefficacy of β-sitosterol in reducing hypercholesterolemia, additionalantiviral, antifungal, and anti-inflammatory properties have beenstudied and observed.

Tocopherols: Antioxidant properties of alpha and gama tocopherols havebeen known and exploited for some time.

Terpenes: pharmacological properties of β-caryophyllene would includeanti-inflammatoryand cytoprotective activities which may too be activein the seed oil.

Methyl salicylate: a compound that exhibits antipyretic,anti-inflammatory and analgesic properties.

Hemp oil or hempseed oil is obtained by pressing hemp seeds. Coldpressed, unrefined hemp oil is dark to clear light green in color, witha pleasant nutty flavor. The darker the color, the grassier the flavor.While most hemp oil is produced from strains of Cannabis sativia thatproduce low levels of THC, we can include in some of our formulationshemp oil from strains of Cannabis indica.

Refined hempseed oil is clear and colorless, with little flavor andlacks natural vitamins and antioxidants. Refined hempseed oil isprimarily used in body care products. Industrial hempseed oil is used inlubricants, paints, inks, fuel, and plastics. Hempseed oil has foundsome limited use in the production of soaps, shampoos and detergents.The oil is of high nutritional value because of its 3:1 ratio of omega-6to omega-3 essential fatty acids, which matches the balance required bythe human body. It has also received attention in recent years as apossible feedstock for the large-scale production of biodiesel. Thereare a number of organizations that promote the production and use ofhempseed oil.

Hempseed oil is generally manufactured from varieties of Cannabis sativathat do not contain significant amounts of THC, the psychoactive elementpresent in the cannabis plant. This manufacturing process typicallyincludes cleaning the seed to 99.99% before pressing the oil. There isno THC within the hempseed, although trace amounts of THC may be foundin hempseed oil when plant matter adheres to the seed surface duringmanufacturing. The modern production of hempseed oil, particularly inCanada, has successfully lowered THC values since 1998. Regularaccredited sampling of THC in Canadian hemp seed oil shows THC levelsusually below detection limit of 4 ppm (parts per million, or 4 mg/kg).Legal limit for THC content in foodstuffs in Canada is 10 ppm. SomeEuropean countries have limits of 5ppm or none-detected, some EUcountries do not have such limits at all. For some products productionof hemp oil from Cannabis species and strains that produce THC isdesirable. Hemp oil is of high nutritional value because of its 3:1ratio of omega-6 to omega-3 essential fatty acids,

About 30-35% of the weight of hempseed is an edible oil that containsabout 80% as essential fatty acids (EFAs); i.e., linoleic acid, omega-6(LA, 55%), α-linolenic acid, omega-3 (ALA, 22%), in addition toγ-linolenic acid, omega-6 (GLA, 1-4%) and stearidonic acid, omega-3(SDA, 0-2%). The proportions of linoleic acid and α-linolenic acid inone tablespoon per day (15 ml) of hempseed oil easily provide humandaily requirements for EFAs. Unlike flaxseed oil, hempseed oil can beused continuously without developing a deficiency or other imbalance ofEFAs. This has been demonstrated in a clinical study, where the dailyingestion of flaxseed oil decreased the endogenous production of GLA.

Hash oil, not to be confused with hempseed oil, is used for bothmedicinal and recreational purposes and made from the mature femaleflowers and leaves of the drug cannabis, thus having a much higher THCcontent. Hash oil should not be confused with hemp, as the modern usageof the word ‘hemp’ is reserved for plants that meet the legalrequirement of containing 0.3% THC or less.

Hash oil (also known as honey oil, dabs, shatter, or earwax) is aresinous matrix of cannabinoids obtained from the cannabis plant bysolvent extraction. Hash oil is the most potent of three main cannabisproducts, which are herb (marijuana), resin (hashish), and oil (hashoil).

Reported THC contents vary between sources. The 2009 World Drug Reportsreports THC content as “may exceed 60%”. A 2013 American forensicscience book gave a range of 10-30% delta-9 THC by weight. A 1972American forensic journal reported a range of 20-65%.

Hash oil is a cannabis product obtained from separating resins fromleaves by solvent extraction. Cannabis is boiled in a solvent to form aviscous liquid which is then strained and the solvent is evaporated toyield hash oil. Flammable solvents used in extraction makes the processdangerous. Newer methods like CO₂ extraction provide a safer way toextract the resin. CO₂ extraction is a method of using high pressure toforce a solvent through plant matter. The solvent used for extraction iscarbon dioxide. The solvent is pushed through the plant matter at a highpressure and separates the cannabinoid resins and terpenes from theplant matter. The result is pure, transparent, amber oil. Carbon dioxideis a natural product which leaves behind no residues. The purity of CO₂is its biggest advantage over all other solvents used for plantextraction. Currently, a popular extraction solvent is butane which canpotentially leave heavy metals behind in the extracted product.

Hashish, often known as “hash”, is a cannabis product composed ofcompressed or purified preparations of stalked resin glands, calledtrichomes, collected from the unfertilized buds of the cannabis plant.It contains the same active ingredients—such as THC and othercannabinoids—but in higher concentrations than unsifted buds or leaves.

Hashish may be solid or resinous depending on the preparation; pressedhashish is usually solid, whereas water-purified hashish—often called“bubble melt hash”—is often a paste-like substance with varying hardnessand pliability, its color most commonly light to dark brown but varyingtoward green, yellow, black or red.[citation needed] It is consumed bybeing heated in a pipe, hookah, bong, bubbler, vaporizer, hot knife(placed between the tips of two heated knife blades), smoked in joints,mixed with cannabis buds or tobacco (the latter being more common inEurope, South America as Brazil and Africa), or cooked in foods. Hashishuse as a medicine and recreational drug dates back to at least the 3rdmillennium BC.

With a view to the foregoing, the present inventors have formulatedcompositions that comprise a Cannabis derived botanical drug product.The US Food and Drug Administration has defined Botanical Drug Productas follows:

-   -   A botanical drug product consists of vegetable materials, which        may include plant materials, algae, macroscopic fungi, or        combinations thereof; or    -   A botanical drug product may be available as (but not limited        to) a solution (e.g., tea), powder, tablet, capsule, elixir,        topical, or injection.

Botanical drug products often have unique features, for example, complexmixtures, lack of a distinct active ingredient, and substantial priorhuman use. Fermentation products and highly purified or chemicallymodified botanical substances are not considered botanical drugproducts.

As used herein and unless otherwise indicated, the term “Cannabisderived biological drug product” is prepared form varieties of Cannabisindica and sativia, which include oils pressed from the seeds; powdersprepared for various plant parts including flowers, leaves, stems, buds,and trichomes; extracts prepared from the various parts includingflowers, leaves, stems, buds, and trichomes, which includes extractsprepared using organic solvents, water extraction, alcohol extracts, andliquid carbon dioxide extracts; hemp oil; hashish oil; hashish; andfractions of extracts or oils prepared by chromatography, phasepartition, temperature fractionation, distillation or other methodsemployed for fractionation.

Most preferably, the term “a Cannabis derived botanical drug product”refers to the compounds obtained from chemical extraction of Cannabis,provided that at least one of THC and CBD is present in the Cannabisderived botanical drug product.

One embodiment of the present invention is a topical formulationcomprising a Cannabis derived botanical drug product, wherein theconcentration of tetrahydrocannabinol in the topical formulation isgreater than 2 milligrams per kilogram.

Another embodiment of the present invention is a topical formulationcomprising a Cannabis derived botanical drug product, wherein theconcentration of cannabidiol in the topical formulation is greater than2 milligrams per kilogram.

Another embodiment of the present invention is a topical formulationcomprising a Cannabis derived botanical drug product, wherein theconcentration of each, cannabidiol and tetrahydrocannabinol, in thetopical formulation is greater than 2 milligrams per kilogram.

Preferably, the amount of tetrahydrocannabinol in the topicalformulation according to the present invention is from 2 to 100milligrams per kilogram, more preferably from 2 to 50 milligrams perkilogram, and more preferably from 2 to 25 milligrams per kilogram. Themost preferred amount of tetrahydrocannabinol in the topical formulationaccording to the present invention is from 2 to 10 milligrams perkilogram. All rational numbers between the preceding minima and maximaare included in the ranges.

Preferably, the amount of cannabidiol in the topical formulationaccording to the present invention is from 2 to 100 milligrams perkilogram, more preferably from 2 to 50 milligrams per kilogram, and morepreferably from 2 to 25 milligrams per kilogram. The most preferredamount of cannabidiol in the topical formulation according to thepresent invention is from 2 to 10 milligrams per kilogram. All rationalnumbers between the preceding minima and maxima are included in theranges.

Preferably, the amount of each of tetrahydrocannabinol and cannabidiol,independently, in the topical formulation according to the presentinvention is from 2 to 100 milligrams per kilogram, more preferably from2 to 50 milligrams per kilogram, and more preferably from 2 to 25milligrams per kilogram. The most preferred amount of each oftetrahydrocannabinol and cannabidiol, independently, in the topicalformulation according to the present invention is from 2 to 10milligrams per kilogram. All rational numbers between the precedingminima and maxima are included in the ranges.

In some embodiments of the present invention, the topical formulationfurther comprises hydrocortisone or any steroid within Groups Ito VII inthe US classification system. Group I steroids include, but are notlimited to, clobetasol propionate, betamethasone dipropionate,halobetasol, and diflorasone diacetate. Group II steroids include, butare not limited to, fluocinonide, halcinonide, amcinonide, anddesoximetasone. Group III steroids include, but are not limited to,triamcinolone acetonide, mometasone furoate, fluticasone propionate,betamethasone dipropionate, and halometasone. Group IV steroids include,but are not limited to, fluocinolone acetonide, hydrocortisone valerate,hydrocortisone butyrate, flurandrenolide, triamcinolone acetonide, andmometasone furoate. Group V steroids include, but are not limited to,fluticasone propionate, desonide, fluocinolone acetonide, andhydrocortisone valerate. Group VI steroids include, but are not limitedto, alclometasone dipropionate, triamcinolone acetonide, fluocinoloneacetonide, and desonide. Group VII steroids include, but are not limitedto, hydrocortisone (2.5%) and hydrocortisone (1%). The amount ofhydrocortisone or steroid within Groups I to VII in the topicalformulation is not particularly limited, so long as it is atherapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises an antibiotic compound. The antibiotic compound is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of ampicillin, bacampicillin, carbenicillinindanyl, mezlocillin, piperacillin, ticarcillin, amoxicillin-clavulanicacid, ampicillin-sulbactam, benzylpenicillin, cloxacillin,dicloxacillin, methicillin, oxacillin, penicillin G, penicillin V,piperacillin tazobactam, ticarcillin clavulanic acid, nafcillin,procaine penicillin, cefadroxil, cefazolin, cephalexin, cephalothin,cephapirin, cephradine, cefaclor, cefamandol, cefonicid, cefotetan,cefoxitin, cefprozil, ceftmetazole, cefuroxime, loracarbef cefdinir,ceftibuten, cefoperazone, cefixime, cefotaxime, cefpodoxime proxetil,ceftazidime, ceftizoxime, ceftriaxone, cefepime, azithromycin,clarithromycin, clindamycin, dirithromycin, erythromycin, lincomycin,troleandomycin, cinoxacin, ciprofloxacin, enoxacin, gatifloxacin,grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, oxolinic acid,gemifloxacin, perfloxacin, imipenem-cilastatin, meropenem, andaztreonam. The amount of the antibiotic compound in the topicalformulation is not particularly limited, so long as it is atherapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises an antiseptic compound. The antiseptic compound is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of iodine, manuka honey, octenidinedihydrochloride, phenol, polyhexanide, sodium chloride, sodiumhypochlorite, calcium hypochlorite, sodium bicarbonate, methyl paraben,and sodium dehydroacetate. The amount of the antiseptic compound in thetopical formulation is not particularly limited, so long as it is atherapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises an antifungal agent. The antifungal agent is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of amphotericin B, candicidin, filipin,hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole,clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole,luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole,sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole,itraconazole, posaconazole, ravuconazole, terconazole, voriconazole,abafungin, amorolfin, butenafine, naftifine, terbinafine, anidulafungin,caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine,griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet,and balsam of Peru. The amount of the antifungal agent in the topicalformulation is not particularly limited, so long as it is atherapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises an anti-acne compound. The anti-acne agent is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of salicylic acid and benzoyl peroxide. Theamount of the anti-acne compound in the topical formulation is notparticularly limited, so long as it is a therapeutically effectiveamount. A preferred amount is from 0.01 to 5 wt %, relative to the totalamount of the topical formulation, more preferably from 0.1 to 1 wt %,relative to the total amount of the topical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises a humectant, which can be referred to as a soothing,smoothing, moisturizing or protective agent. The humectant is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of calamine, dodecylsulphate, sodium laurylsulphate (SLS), a polyoxyethylene ester of polysorbitan, such asmonooleate, monolaurate, monopalmitate, monostearate esters, esters ofsorbitan, the polyoxyethylenes ethers, the sodium dioctylsulphosuccinate(DOSS), lecithin, and sodium docusate. Sodium lauryl sulphate andcalamine are the most preferred humectants. The amount of the humectantin the topical formulation is not particularly limited, so long as it isa therapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises a UV-absorbing compound, which can be referred to as asunscreen agent. The UV-absorbing compound is not particularly limited,and is preferably at least one member selected from the group consistingof glyceryl PABA, padimate O, roxadimate, dioxybenzone, oxybenzone,sulisonbenzone, octocrylene, octyl methoxycinnamate, ethoxyethylp-methoxycinnamate, homomenthyl salicylate, ethylhexyl salicylate,trolamine salicylate, avobenzone, ecamsule, ensulizole, bemotrizinol,and bisoctrizole. The amount of the UV-absorbing compound in the topicalformulation is not particularly limited, so long as it is atherapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises an analgesic agent. The analgesic agent is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of methyl salicylate, codeine, morphine,methadone, pethidine, buprenorphine, hydromorphine, levorphanol,oxycodone, fentanyl, and a non-steroidal anti-inflammatory drug. Theamount of the analgesic agent in the topical formulation is notparticularly limited, so long as it is a therapeutically effectiveamount. A preferred amount is from 0.01 to 5 wt %, relative to the totalamount of the topical formulation, more preferably from 0.1 to 1 wt %,relative to the total amount of the topical formulation.

In some embodiments of the present invention, the topical formulationfurther comprises an anti-viral compound. The anti-viral compound is notparticularly limited, and is preferably at least one member selectedfrom the group consisting of acyclovir, famciclovir, penciclovir,valacyclovir, trifluridine, docosanol, amantadine, rimantadine,oseltamivir, and zanamivir. The amount of the anti-viral compound in thetopical formulation is not particularly limited, so long as it is atherapeutically effective amount. A preferred amount is from 0.01 to 5wt %, relative to the total amount of the topical formulation, morepreferably from 0.1 to 1 wt %, relative to the total amount of thetopical formulation.

The form of the topical formulations of the present invention is notparticularly limited, provided that it is in a form that promotes itsuse as a topical formulation. Non-limiting examples of the form includea lotion, a cream, a salve, a liniment, an ointment, a gel, a paste, atonic, an unguent, a nasal spray, a soap, a shampoo, and a lip balm.

Unless otherwise indicated, the term “cream” as used herein relates toan emulsion of oil and water in approximately equal proportions, whichpenetrates stratum corneum outer layer of skin well. Creams are usuallytopical preparations for application to the skin. Creams for applicationto mucus membranes such as those of the rectum or vagina are also used.Creams may be considered pharmaceutical products as even cosmetic creamsare based on techniques developed by pharmacy and unmedicated creams arehighly used in a variety of skin conditions (dermatoses). The use of thefinger-tip unit concept may be helpful in guiding how much topical creamis required to cover different areas. Creams are usually semi-solidemulsions that are mixtures of oil and water. They are divided into twotypes: oil-in-water (O/W) creams, which are composed of small dropletsof oil dispersed in a continuous phase; and water-in-oil (W/O) creams,which are composed of small droplets of water dispersed in a continuousoily phase. Oil-in-water creams are more comfortable and cosmeticallyacceptable as they are less greasy and more easily washed off usingwater. Water-in-oil creams are more difficult to handle but many drugswhich are incorporated into creams are hydrophobic and will be releasedmore readily from a water-in-oil cream than an oil-in-water cream.Water-in-oil creams are also more moisturizing as they provide an oilybarrier which reduces water loss from the stratum corneum, the outermostlayer of the skin.

Creams can provide a barrier to protect the skin. This may be a physicalbarrier or a chemical barrier as with UV-absorbing compounds. To aid inthe retention of moisture (especially water-in-oil creams), creams areusually used for a variety of purposes including cleansing, emollienteffects, and as a vehicle for drug substances such as local anesthetics,anti-inflammatories (NSAIDs or corticosteroids), hormones, antibiotics,antifungals or counter-irritants, and cannabis derived botanical drugproduct.

Liniments usually refer to topical formulations for application to theskin. Preparations of this type are also called balm. Liniments are of asimilar viscosity to lotions (being significantly less viscous than anointment or cream) but unlike a lotion a liniment is applied withfriction; that is, a liniment is always rubbed into the skin. Linimentsare typically sold to relieve pain and stiffness, such as from soremuscles or from arthritis. These liniments typically are formulated fromalcohol, acetone, or similar quickly evaporating solvents and usuallycomprise counterirritant aromatic chemical compounds such as methylsalicilate, benzoin resin, or capsaicin. Liniments are a commonsubstance used by trainers and owners of horses. They may be applieddiluted or full-strength, usually added into a bucket of water whensponged on the body. Liniments are especially useful in hot weather tohelp a hot horse cool down: the alcohols help the product to quicklyevaporate, and the oils they contain cause the capillaries in the skinto dilate, also increasing the cooling process.

Unless otherwise indicated, the term “ointment” relates to compositionswhere oil and water are present in a ratio of from 7:1 to 2:1,preferably, from 5:1 to 3:1, most preferably about 4 parts to one.Ointments provide barrier against moisture loss. Usually, ointments areformulations using oils, waxes, water, alcohols, petroleum products,water, and other agents to prepare formulations with various viscositiesand solvent properties. Commonly used formulations include oleaginousbase (White Ointment), absorption base, W/O emulsion base (Cold Creamtype base), O/W emulsion base (Hydrophilic Ointment), water solublebase, in addition to others. These preparations are used to dissolve orsuspend substances or products with medicinal or cosmetic value. Theseformulations are suited for incorporation Cannabis derived botanicaldrug product alone or with the addition of other substances.

Unless otherwise indicated, the term “gel” relates to compositions thatliquefy upon contact with the skin.

Unless otherwise indicated, the term “paste” relates to compositionswhere at least the three following agents—oil, water, and powder—arecombined; an ointment in which a powder is suspended.

Unless otherwise indicated, the term “lotion” relates to a low- tomedium-viscosity topical preparation intended for application tounbroken skin in contrast, creams and gels have higher viscosity.Lotions are applied to external skin with bare hands, a clean cloth,cotton wool or gauze. Many lotions, especially hand lotions and bodylotions are formulated not as a medicine delivery system, but simply tosmooth, re-hydrate, and soften the skin. These are particularly popularwith the aging and aged demographic groups, and in the case of faceusage, can also be classified as a cosmetic in many cases, and maycontain fragrances.

Most lotions are oil-in-water emulsions using a substance such as cetylalcohol to keep the emulsion together, but water-in-oil lotions are alsoformulated. The key components of a skin care lotion, cream or gelemulsion (that is mixtures of oil and water) are the aqueous and oilphases, an emulsifier to prevent separation of these two phases, and, ifused, the drug substance or substances. Other ingredients are commonlyadded to lotions, such as fragrances, glycerol, petroleum jelly, dyes,preservatives, proteins and stabilizing agents. Lotions can be used forthe delivery to the skin of medications such as: antibiotics;antiseptics; antifungals; corticosteroids; anti-acne agents; andsoothing, smoothing, moisturizing or protective agents.

In some embodiments of the present invention, the same drug ingredientcan be formulated into a lotion, cream and ointment. Creams are the mostconvenient of the three but are inappropriate for application to regionsof hairy skin such as the scalp, while a lotion is less viscous and maybe readily applied to these areas (many medicated shampoos are in factlotions). Non-comedogenic lotions are recommended for use on acne proneskin.

In some embodiments of the present invention, formulations containingCannabis derived botanical drug product include preparations where allor part of the oil component is hemp oil. These preparations may alsocomprise any of the other Cannabis derived botanical drug products toprovide benefit inherent to these materials, such as antibiotics;antiseptics; antifungals; corticosteroids; anti-acne agents; andsoothing, smoothing, moisturizing or protective agents.

In some embodiments, the topical formulations can be in the form of anasal spray, which usually comprise decongestants and other medicationsto treat rhinitis, allergy, other conditions associated with swollentissue and fluid secretion. Nasal sprays are usually applied directly tothe nasal cavity. By applying them directly to the site of action,topical decongestants relieve nasal congestion while reducing the sideeffects associated with systemically-acting decongestants, such as highblood pressure. Topical decongestants are a common form of nasal relief,due to their quick effects which can clear the sinus in quickly.

In some embodiments, the topical formulations can be in the form of asoap, which are formulations that comprise a salt of a fatty acid. Soapsare mainly used as surfactants for washing, bathing, and cleaning, butthey are also used in textile spinning and are important components oflubricants. Soaps for cleansing are usually obtained by treatingvegetable or animal oils and fats with a strongly alkaline solution.Fats and oils are composed of triglycerides; three molecules of fattyacids are attached to a single molecule of glycerol. The alkalinesolution, which is often called lye (although the term “lye soap” refersalmost exclusively to soaps made with sodium hydroxide), is believed topromote a chemical reaction known as saponification. In saponification,the fats are first hydrolyzed into free fatty acids, which then combinewith the alkali to form crude soap. Glycerol (glycerine) is usuallyliberated and is either left in or washed out and recovered as a usefulbyproduct, depending on the process employed.

In some embodiments, the topical formulations can be in the form of ashampoo, which is a hair care product used for the removal of oils,dirt, skin particles, dandruff, environmental pollutants and othercontaminant particles that gradually build up in hair. A goal may be toremove the unwanted build-up without stripping out so much sebum as tomake hair unmanageable.

Another embodiment of the present invention is a method of making thetopical formulation in the form of a cream, which comprises (i)dispersing lake/powder into mineral oil or silicone oil to obtain an oilphase; (ii) dispersing an emulsifier, a thickener; and a stabilizer intowater in a separate vessel to obtain an aqueous phase; (iii) blendingthe oil phase and the aqueous phase to form an emulsion; and (iv)dispersing an active ingredient such as a Cannabis derived botanicaldrug product into at least one of the oil phase, the aqueous phase, andthe emulsion. In some embodiments, the method further comprises heatingduring at least one of (i) dispersing lake/powder into mineral oil orsilicone oil to obtain an oil phase and (ii) dispersing an emulsifier, athickener; and a stabilizer into water in a separate vessel to obtain anaqueous phase. Temperatures of this heating are not particularlylimited, so long as the oil phase and the aqueous phase result from thedispersing.

Another embodiment of the present invention is a method of making thetopical formulation in the form of a lotion, which comprises mixing anoil phase comprising hemp oil with an emulsifier and with an aqueousphase to form a mixture and heating said mixture at a temperature offrom 45 and 85° C. to form an aqueous emulsion. Emulsifiers include, butare not limited to, cetyl alcohol, stearic acid, and a mixture thereof.The water phase comprises a stabilizing agent such as VEEGUM® orCARBOPOL®.

Another embodiment of the present invention is a method of making thetopical formulation in the form of a shampoo, which comprises combininga surfactant, most often sodium lauryl sulfate and/or sodium laurethsulfate with a co-surfactant, most often cocamidopropyl betaine, in anaqueous phase and mixing the aqueous phase to form a thick, viscousliquid. Preferred methods further comprise adding other ingredients,such as salt (sodium chloride), a preservative, and fragrance, to theaqueous phase.

Another embodiment of the present invention is a method of treating adermatological disease, which comprises applying a therapeuticallyeffective amount of the topical formulation according to the presentinvention to skin affected with a dermatological disease. Non-limitingexamples of targeted dermatological diseases include eczema, psoriasis,sunburn, contact dermatitis, poison ivy and conditions caused by otherplant materials containing urushiol or related molecules, type 1 andtype 2 herpes, insect bites, anal itching, vaginal itching, acne, wartsand other acute and chronic dermatoses afflicting humans, and use as atopical analgesic for muscle and arthritic pain. Psoriasis is thepreferred targeted dermatological disease.

Additionally, formulations can be tailored and used to treat veterinarydermatoses including seborrhea, keratinization, ichthyosis, sebaceousadenitits, among other hair and dermatological disease occurring inanimals. Cosmetic formulations including lotions, creams, soaps,shampoos, lip balms are that are designed for moisturizing, anti-aging,anti-wrinkle, acne treatment, rough skin treatment, and dandruff.

Unless indicated otherwise, the term “therapeutically effective amount”is not particularly limited, so long as at least one of THC and CBD ispresent in an amount effective for treating the dermatological disease.Preferably, the therapeutically effective amount of at least one of THCand CBD is from 2 to 100 milligrams per kilogram, more preferably from 2to 50 milligrams per kilogram, and more preferably from 2 to 25milligrams per kilogram. The most preferred therapeutically effectiveamount of THC and/or CBD in the topical formulation according to thepresent invention is from 2 to 10 milligrams per kilogram. All rationalnumbers between the preceding minima and maxima are included in theranges.

EXAMPLES

The following non-limiting examples are intended to illustrate thepresent invention.

Example 1: Moisturizing Lotion

A lotion is formulated by mixing an emulsifier with hemp oil itself orby mixing hemp oil and at least one other oil to produce an emulsionwith water. An emulsifier such as cetyl alcohol or stearic acid wasadded to the oil phase. The water phase is prepared separately andcontains stabilizing agents such as VEEGUM® or CARBOPOL®. The mixture isheated to between 45 and 85° C. and mix until a stable emulsion isformed.

Example 2: Moisturizing Lotion with CBD

A lotion is prepared as described in Example 1. Another Cannabis derivedBotanic drug product is added to either the water phase or the oil phaseto achieve a CBD concentration of 2 mg per kilogram or more in the finalproduct.

Example 3: Moisturizing Lotion with CBD

A Cannabis derived botanic drug Product is added to a commerciallyavailable lotion base to achieve a CBD concentration of 2 mg perkilogram or more in the final lotion.

Example 4: Moisturizing Lotion with THC

A lotion is prepared as described in Example 1. Another Cannabis derivedbotanic drug product is added to either the water phase or the oil phaseto achieve a THC concentration of 2 mg per kilogram or more in the finalproduct.

Example 5: Moisturizing Lotion with THC

A Cannabis derived botanic drug product is added to commerciallyavailable lotion base to achieve a THC concentration of 2 mg perkilogram or more in the final product.

Example 6: Multi-Action Lotion

A lotion is prepared as described in Example 1. Another Cannabis derivedbotanic drug product is added to either the water phase or the oil phaseto achieve a CBD concentration of 2 mg per kilogram or more in the finalproduct and the THC concentration of 2 mg per kilogram or more in thefinal product.

Example 7: Multi-Action Lotion

A Cannabis derived botanic drug product is added to commerciallyavailable lotion base to achieve a CBD concentration of 2 mg perkilogram or more in the final product and the THC concentration of 2 mgper kilogram or more in the final product.

Example 8: Anti-Pruritic Lotion

A lotion is prepared as in Example 4 or Example 5 above. Benzocaine isadded to the preparation to enhance the anti-puritic properties of theproduct

As noted above, lotions targeted to a wide variety of medicinal uses canbe prepared using the described methodology and where appropriate theaddition of other agents to the preparation may supplement thepharmacologic actions of the Cannabis derived botanical drug product.Options for preparation of lotions include formulations as described inExamples 2, 3, 4, 5, and 6 where no hemp oil is used.

Example 9: Anti-Inflammatory Cream

A cream is prepared as described above and Cannabis derived botanic drugproduct is added to achieve CBD and/or THC levels of greater than 2mg/kg of final product.

Example 10: Feminine Hygene Cream

A cream is prepared as described in Example 9 with benzocaine andresorcinol incorporated in a therapeutically effective amount.

Example 11: Fortified Anti-inflammatory Cream

A cream is formulated as in Example 9 with a therapeutically effectiveamount of hydrocortisone or any of the other steroid within Groups ItoVII in the US classification system incorporated into the cream.

Example 12: Arthritis Cream

A cream is formulated as in Example 9 with a therapeutically effectiveamount of methyl salicylate and menthol incorporated into the cream.

Example 13: Fever Sore Ointment

A Cannabis derived botanical drug product is dispersed in O/W emulsionbase (Hydrophilic Ointment) so that the concentration for both THC andCBD in the emulsion is greater than 2 mg/kg.

Example 14: Extra Strength Fever Sore Ointment

An ointment is prepared as described in Example 13 but includes theaddition of dimethicone, camphor, menthol, and phenol in the ointment.

Example 15: Veterinary Liniment

A formulation is prepared that comprises hemp oil, alcohol, and anessential oil such a eucalyptus and menthol.

Example 16: Equine Liniment

A formulation as described Example 15 is prepared and also compriseswitch hazel and Cannabis derived botanical drug product so that theconcentration for both THC and CBD is greater than 2 mg/kg.

Example 17: Veterinary Herbal Tonic

An emulsion is prepared using hemp oil and stabilizing agents. Cannabisderived Botanic Drug Product is included in the emulsion to achieve THCand or CDD concentrations of more than 2 mg/kg.

Example 18: Nasal Spray

A Cannabis derived botanic drug substance is dispersed in a solutioncontaining a combination of excipients which may include cellulose,glycerol, sodium citrate, citric acid monohydrate, polysorbate 80,benzalkonium chloride, purified water. The final product contains CBDand/or THC at concentrations of more than 2 mgc/kg. This solution isdispensed into containers that facilitate spraying an aerosol into thenasal cavity.

Example 19: Cannabis Herbal Soap

A soap is prepared by standard saponification of oils and fats that mayinclude hemp oil. As the preparation is cooling Cannabis derivedbotanical drug product is added to the soap to achieve THC and or CDBconcentrations of greater than 2 mg/kg.

Example 20: Cannabis Herbal Glycerin Soap

A Cannabis derived botanical drug product is formulated withcommercially available glycerin soap base to achieve final CBD and/orTHC concentrations of more than 2 mg/kg.

Example 21: Cannabis Herbal Shampoo

A Cannabis derived botanical drug product is formulated withcommercially available Shampoo base to achieve final CBD and/or THCconcentrations of more than 2 mg/kg. Essential oils and perfumes may beadded.

Example 22: Lip Balm

A commercially available lip balm is supplemented with a Cannabisderived botanical drug product is added to achieve THC and or CDBconcentrations of greater than 2 mg/kg.

Example 23: Sunscreen

A sunscreen formulation is prepared as a lotion described in Example 1,2, 3, 4, or 5 above and comprises a sun-blocking agent as described in:Title 21—Food And Drugs; Chapter I—Food And Drug Administration;Department Of Health And Human Services Subchapter D—Drugs For HumanUse; Part 352 Sunscreen Products for Over-The-Counter Use.

1. A topical formulation, comprising: an extract of cannabis sativa orcannabis indica: at least one compound selected from the groupconsisting of menthol, resorcinol, and phenol, present in an amount ofat least 0.1 wt % in the topical formulation, wherein a concentration ofat least one component selected from the group consisting oftetrahydrocannabinol and cannabidiol in the topical formulation isgreater than 2 milligrams per kilogram.
 2. The topical formulation ofclaim 1, wherein the extract is an extract of cannabis sativa.
 3. Thetopical formulation of claim 1, wherein the extract is an extract ofcannabis indica.
 4. The topical formulation of claim 1, wherein theconcentration of the at least one selected from the group consisting oftetrahydrocannabinol and cannabidiol in the topical formulation is from2 to 100 milligrams per kilogram.
 5. The topical formulation of claim 1,wherein the concentration of the at least one selected from the groupconsisting of tetrahydrocannabinol and cannabidiol in the topicalformulation is from 2 to 25 milligrams per kilogram.
 6. The topicalformulation of claim 1, comprising from 0.1-5 wt %, based on a totalweight of the topical formulation, of the at least one compound selectedfrom the group consisting of menthol, resorcinol, and phenol.
 7. Thetopical formulation of claim 1, comprising from 0.1-1 wt %, based on atotal weight of the topical formulation, of the at least one compoundselected from the group consisting of menthol, resorcinol, and phenol.8. The topical formulation of claim 1, wherein the compound is menthol.9. The topical formulation of claim 1, wherein the compound isresorcinol.
 10. The topical formulation of claim 1, wherein the compoundis phenol.
 11. The topical formulation of claim 1, consistingessentially of: the extract of cannabis sativa or cannabis indica; andthe at least one compound selected from the group consisting of menthol,resorcinol, and phenol, wherein the topical formulation is obtained bydispersing the extract of cannabis sativa or cannabis indica in awater-in-oil emulsion, an oil-in-water emulsion, a wax-in-oil base, anoil-in-wax base, or a liniment consisting essentially of the at leastone compound selected from the group consisting of menthol, resorcinol,and phenol.